Role of cellular senescence in inflammation and regeneration.

Cellular senescence is the state in which cells undergo irreversible cell cycle arrest and acquire diverse phenotypes. It has been linked to chronic inflammation and fibrosis in various organs as well as to individual aging. Therefore, eliminating senescent cells has emerged as a potential target for extending healthy lifespans. Cellular senescence plays a beneficial role in many biological processes, including embryonic development, wound healing, and tissue regeneration, which is mediated by the activation of stem cells. Therefore, a comprehensive understanding of cellular senescence, including both its beneficial and detrimental effects, is critical for developing safe and effective treatment strategies to target senescent cells. This review provides an overview of the biological and pathological roles of cellular senescence, with a particular focus on its beneficial or detrimental functions among its various roles.

Cellular senescence and wound healing in aged and diabetic skin.

Cellular senescence is a biological mechanism that prevents abnormal cell proliferation during tissue repair, and it is often accompanied by the secretion of various factors, such as cytokines and chemokines, known as the senescence-associated secretory phenotype (SASP). SASP-mediated cell-to-cell communication promotes tissue repair, regeneration, and development. However, senescent cells can accumulate abnormally at injury sites, leading to excessive inflammation, tissue dysfunction, and intractable wounds. The effects of cellular senescence on skin wound healing can be both beneficial and detrimental, depending on the condition. Here, we reviewed the functional differences in cellular senescence that emerge during wound healing, chronic inflammation, and skin aging. We also review the latest mechanisms of wound healing in the epidermis, dermis, and subcutaneous fat, with a focus on cellular senescence, chronic inflammation, and tissue regeneration. Finally, we discuss the potential clinical applications of promoting and inhibiting cellular senescence to maximize benefits and minimize detrimental effects.

Senescence-associated secretory phenotypes in mesenchymal cells contribute to cytotoxic immune response in oral lichen planus.

Oral lichen planus is a chronic inflammatory condition that adversely affects the oral mucosa; however, its etiology remains elusive. Consequently, therapeutic interventions for oral lichen planus are limited to symptomatic management. This study provides evidence of the accumulation of senescent mesenchymal cells, CD8 + T cells, and natural killer cells in patients with oral lichen planus. We profiled the patients' tissues using the National Center for Biotechnology Information Gene Expression Omnibus database and found that senescence-related genes were upregulated in these tissues by gene set enrichment analysis. Immunohistochemical analysis showed increased senescent mesenchymal cells in the subepithelial layer of patients with oral lichen planus. Single-cell RNA-seq data retrieved from the Gene Expression Omnibus database of patients with oral lichen planus revealed that mesenchymal cells were marked by the upregulation of senescence-related genes. Cell-cell communication analysis using CellChat showed that senescent mesenchymal cells significantly influenced CD8 + T cells and natural killer cells via CXCL12-CXCR4 signaling, which is known to activate and recruit CD8 + T cells and NK cells. Finally, in vitro assays demonstrated that the secretion of senescence-associated factors from mesenchymal cells stimulated the activation of T cells and natural killer cells and promoted epithelial cell senescence and cytotoxicity. These findings suggest that the accumulation of mesenchymal cells with senescence-associated secretory phenotype may be a key driver of oral lichen planus pathogenesis.

Fisetin reduces the senescent tubular epithelial cell burden and also inhibits proliferative fibroblasts in murine lupus nephritis.

Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease characterized by the involvement of multiple organs. Lupus nephritis (LN) is a major risk factor for overall morbidity and mortality in SLE patients. Hence, designing effective drugs is pivotal for treating individuals with LN. Fisetin plays a senolytic role by specifically eliminating senescent cells, inhibiting cell proliferation, and exerting anti-inflammatory, anti-oxidant, and anti-tumorigenic effects. However, limited research has been conducted on the utility and therapeutic mechanisms of fisetin in chronic inflammation. Similarly, whether the effects of fisetin depend on cell type remains unclear. In this study, we found that LN-prone MRL/lpr mice demonstrated accumulation of Ki-67-positive myofibroblasts and p15INK4B-positive senescent tubular epithelial cells (TECs) that highly expressed transforming growth factor ß (TGF-ß). TGF-ß stimulation induced senescence of NRK-52E renal TECs and proliferation of NRK-49F renal fibroblasts, suggesting that TGF-ß promotes senescence and proliferation in a cell type-dependent manner, which is inhibited by fisetin treatment in vitro. Furthermore, fisetin treatment in vivo reduced the number of senescent TECs and myofibroblasts, which attenuated kidney fibrosis, reduced senescence-associated secretory phenotype (SASP) expression, and increased TEC proliferation. These data suggest that the effects of fisetin vary depending on the cell type and may have therapeutic effects in complex and diverse LN pathologies.

Intrathecal Injection of Mesenchymal Stromal Cell Cultured on 3D Fiber Ameliorates Multiple Organ Damage in Murine Lupus.

Up to 60% of patients with systemic lupus erythematosus (SLE) experience autonomic symptom. Sympathetic nervous system damage can cause dysfunction of the bone marrow that activates inflammatory cells, potentially causing multiple organ damage. We hypothesized that sympathetic nervous system damage would induce bone marrow dysfunction with multiple organ damage in SLE, and that multiple organ damage could be improved by therapy targeting the nervous system. Here, we showed that damage to autonomic nerves and Schwann cells occurred in the bone marrow and central nervous system of SLE model mice. A neurotoxic drug increased mortality and induced severe neuropathy and multiple organ damage, while a neuroprotective drug prevented multiple organ damage. The administration of bone marrow-derived mesenchymal stromal cells (BMSCs) cultured on a 3-dimensional fiber scaffold improved bone marrow neuropathy, skin lesions, kidney function, and mortality. Our results reveal that bone marrow neuropathy influence multiple organ damage associated with SLE, and improvement of bone marrow neuropathy by intrathecal injection of BMSC may be a target for SLE multiple-organ damage.

Altered regulation of mesenchymal cell senescence in adipose tissue promotes pathological changes associated with diabetic wound healing.

Pathologic diabetic wound healing is caused by sequential and progressive deterioration of hemostasis, inflammation, proliferation, and resolution/remodeling. Cellular senescence promotes wound healing; however, diabetic wounds exhibit low levels of senescent factors and accumulate senescent cells, which impair the healing process. Here we show that the number of p15INK4B + PDGFRα + senescent mesenchymal cells in adipose tissue increases transiently during early phases of wound healing in both non-diabetic mice and humans. Transplantation of adipose tissue from diabetic mice into non-diabetic mice results in impaired wound healing and an altered cellular senescence-associated secretory phenotype (SASP), suggesting that insufficient induction of adipose tissue senescence after injury is a pathological mechanism of diabetic wound healing. These results provide insight into how regulation of senescence in adipose tissue contributes to wound healing and could constitute a basis for developing therapeutic treatment for wound healing impairment in diabetes.

Accumulation of Senescent Neural Cells in Murine Lupus With Depression-Like Behavior.

Neuropsychiatric manifestations targeting the central, peripheral, and autonomic nervous system are common in systemic lupus erythematosus (SLE); collectively, these symptoms are termed neuropsychiatric SLE (NPSLE). Among a wide variety of neuropsychiatric symptoms, depression is observed in about 24-39% of SLE patients. Several cytokines and chemokines have been identified as biomarkers or therapeutic targets of NPSLE; in particular, the levels of type 1 interferons, TNFs, and IL-6 are elevated in SLE patient's cerebrospinal fluid (CSF), and these factors contribute to the pathology of depression. Here, we show that senescent neural cells accumulate in the hippocampal cornu ammonis 3 (CA3) region in MRL/lpr SLE model mice with depressive behavior. Furthermore, oral administration of fisetin, a senolytic drug, reduced the number of senescent neural cells and reduced depressive behavior in the MRL/lpr mice. In addition, transcription of several senescence and senescence-associated secretory phenotype (SASP) factors in the hippocampal region also decreased after fisetin treatment in the MRL/lpr mice. These results indicate that the accumulation of senescent neural cells in the hippocampus plays a role in NPSLE pathogenesis, and therapies targeting senescent cells may represent a candidate approach to treat NPSLE.

Diverse Roles of Cellular Senescence in Skeletal Muscle Inflammation, Regeneration, and Therapeutics.

Skeletal muscle undergoes vigorous tissue remodeling after injury. However, aging, chronic inflammatory diseases, sarcopenia, and neuromuscular disorders cause muscle loss and degeneration, resulting in muscular dysfunction. Cellular senescence, a state of irreversible cell cycle arrest, acts during normal embryonic development and remodeling after tissue damage; when these processes are complete, the senescent cells are eliminated. However, the accumulation of senescent cells is a hallmark of aging tissues or pathological contexts and may lead to progressive tissue degeneration. The mechanisms responsible for the effects of senescent cells have not been fully elucidated. Here, we review current knowledge about the beneficial and detrimental effects of senescent cells in tissue repair, regeneration, aging, and age-related disease, especially in skeletal muscle. We also discuss how senescence of muscle stem cells and muscle-resident fibro-adipogenic progenitors affects muscle pathologies or regeneration, and consider the possibility that immunosenescence leads to muscle pathogenesis. Finally, we explore senotherapy, the therapeutic targeting of senescence to treat age-related disease, from the standpoint of improving muscle regeneration.

Bone marrow-derived mesenchymal stem cells improve cognitive impairment in an Alzheimer's disease model by increasing the expression of microRNA-146a in hippocampus.

Alzheimer's disease (AD) is characterized by the accumulation of amyloid-ß and tau. We previously reported that administration of bone marrow mesenchymal stem cells (BM-MSCs) ameliorates diabetes-induced cognitive impairment by transferring exosomes derived from these cells into astrocytes. Here, we show that intracerebroventricularly injected BM-MSCs improve cognitive impairment in AD model mice by ameliorating astrocytic inflammation as well as synaptogenesis. Although AD model mice showed an increase in NF-κB in the hippocampus, BM-MSC-treated AD model mice did not show this increase but showed an increase in levels of microRNA (miR)-146a in the hippocampus. Intracerebroventricularly injected BM-MSCs were attached to the choroid plexus in the lateral ventricle, and thus, BM-MSCs may secrete exosomes into the cerebrospinal fluid. In vitro experiments showed that exosomal miR-146a secreted from BM-MSCs was taken up into astrocytes, and an increased level of miR-146a and a decreased level of NF-κB were observed in astrocytes. Astrocytes are key cells for the formation of synapses, and thus, restoration of astrocytic function may have led to synaptogenesis and correction of cognitive impairment. The present study indicates that exosomal transfer of miR-146a is involved in the correction of cognitive impairment in AD model mice.

Exercise enhances skeletal muscle regeneration by promoting senescence in fibro-adipogenic progenitors.

Idiopathic inflammatory myopathies cause progressive muscle weakness and degeneration. Since high-dose glucocorticoids might not lead to full recovery of muscle function, physical exercise is also an important intervention, but some exercises exacerbate chronic inflammation and muscle fibrosis. It is unknown how physical exercise can have both beneficial and detrimental effects in chronic myopathy. Here we show that senescence of fibro-adipogenic progenitors (FAPs) in response to exercise-induced muscle damage is needed to establish a state of regenerative inflammation that induces muscle regeneration. In chronic inflammatory myopathy model mice, exercise does not promote FAP senescence or resistance against tumor necrosis factor-mediated apoptosis. Pro-senescent intervention combining exercise and pharmacological AMPK activation reverses FAP apoptosis resistance and improves muscle function and regeneration. Our results demonstrate that the absence of FAP senescence after exercise leads to muscle degeneration with FAP accumulation. FAP-targeted pro-senescent interventions with exercise and pharmacological AMPK activation may constitute a therapeutic strategy for chronic inflammatory myopathy.

An enriched environment prevents cognitive impairment in an Alzheimer's disease model by enhancing the secretion of exosomal microRNA-146a from the choroid plexus.

Alzheimer's disease (AD) is characterized by the extensive deposition of amyloid-ß plaques and neurofibrillary tangles. We previously found that preserved function of astrocytes is associated with cognitively normal subjects with AD pathology. Here we show that an enriched environment (EE) can prevent cognitive impairment in AD model mice by ameliorating astrocytic inflammation and increasing synaptic density in the subiculum area of the hippocampus. In AD model mice treated with an EE, increased levels of microRNA (miR)-146a and down-regulation of NF-κB were observed in the hippocampus. In addition, increased levels of interferon (IFN)-γ were seen in serum from mice exposed to an EE. In vitro, enhanced miR-146a expression was observed in exosomes derived from the choroid plexus (CP) after IFN-γ treatment. In further in vitro experiments, we transfected miR-146a into Aß/lipopolysaccharide-induced inflammatory astrocytes and showed that miR-146a ameliorated astrocytic inflammation by down-regulating tumor necrosis factor receptor-associated factor 6 and NF-κB. The present study indicates that following an EE, exosomal miR-146a derived from the CP cells is a key factor in ameliorating astrocytic inflammation, leading to synaptogenesis and correction of cognitive impairment.

Can an insole for obese individuals maintain the arch of the foot against repeated hyper loading?

BACKGROUND: Insoles are often applied as preventive therapy of flatfoot deformity, but the therapeutic effects on obese individuals are still controversial. We aimed to investigate the effect of insole use on time-dependent changes in the foot arch during a repeated-loading simulation designed to represent 20,000 contiguous steps in individuals with a BMI value in the range of 30-40 kg/m2. METHODS: Eighteen cadaveric feet were randomly divided into the following three groups: normal, obese, and insole. Ten thousand cyclic loadings of 500 N (normal group) or 1000 N (obese and insole groups) were applied to the feet. We measured time-dependent change in arch height and calculated the bony arch index (BAI), arch flexibility, and energy absorption. RESULTS: The normal group maintained more than 0.21 BAI, which is the diagnostic criterion for a normal arch, throughout the 10,000 cycles; however, BAI was less than 0.21 at 1000 cycles in the obese group (mean, 0.203; 95% confidence interval [CI] 0.196-0.209) and at 6000 cycles in the insole group (mean, 0.200; 95% CI, 0.191-0.209). Although there was a significant time-dependent decrease in flexibility and energy absorption in both the obese and insole groups (P < 0.001), the difference between 1 and 10,000 cycles were significantly smaller in the insole group than in the obese group (P = 0.024). CONCLUSIONS: Use of insoles for obese individuals may help to slow time-dependent foot structural changes. However, the effect was not enough to maintain the foot structure against repeated hyper loadings.

p16INK4A-expressing mesenchymal stromal cells restore the senescence-clearance-regeneration sequence that is impaired in chronic muscle inflammation.

BACKGROUND: The therapeutic benefits of mesenchymal stromal cells (MSCs) include treatment of chronic inflammation. However, given the short-lived engraftment of these cells in vivo, their therapeutic efficacy remains mysterious. Transient induction of cellular senescence contributes to activation of immune cells, which promotes clearance of damaged cells during tissue remodelling. This may occur in tissue-resident mesenchymal progenitor cells during regeneration. Elucidation of the role of senescence in tissue-resident mesenchymal progenitor cells during regeneration would provide insight into the profile of therapeutic MSCs for treatment of chronic inflammatory disease. METHODS: We evaluated multipotent mesenchymal progenitor cells, termed fibro/adipogenic progenitors (FAPs), and immune cells in acute muscle injury (AMI) model mice and mice with myosin-induced experimental autoimmune myositis, a model of chronic inflammatory myopathy (CIM). Human bone marrow MSCs were optimised for the treatment of CIM using placental extract. FINDING: FAPs in AMI transiently expressed p16INK4A on days 1 and 2 after injury and recruited phagocytic immune cells, whereas in CIM, p16INK4A expression in FAPs was low. Cellular senescence occurs during the natural maturation of the placenta. Therefore, we used human placental extract to induce p16INK4A expression in therapeutic human bone marrow MSCs in culture. Treatment of CIM with p16INK4A-expressing MSCs promoted tissue remodelling by transiently increasing the abundance of engrafted MSCs, inducing cellular senescence in innate FAPs, and recruiting phagocytic immune cells. INTERPRETATION: MSCs may exert their effect by remodelling the chronic inflammatory environment via senescence-related regenerative processes.